Technical Field
The present invention relates to a heterocyclic pyridone compound, an intermediate and a preparation method thereof, a pharmaceutical composition containing the heterocyclic pyridone compound as an active ingredient, and a use of the pharmaceutical composition in treatment of diseases associated with tyrosine kinase c-Met, especially cancer associated with c-Met, as a medicament.
Related Art
Cancer is the number one killer that threatens human life and health worldwide. Although medical advances enable human to have many new methods for treatment of cancer, presently, cancer is still considered as an unsolved medical problem. Cancer may be caused by many causes, and in recent years, people is enabled to gradually clarify the nature of tumor by means of the development of disciplines such as molecular oncology and molecular pharmacology, and people gradually realize that the nature of carcinogenesis is unlimited cell proliferation caused by cellular signaling pathway disorder. As the most important member involved in cellular signaling, protein tyrosine kinases (PTKs, tyrosine kinases for short) are the most common growth factor receptors, and are closely correlated to occurrence and development of tumor. An excessively high activity of tyrosine kinases leads to activation of a downstream signaling pathway, thereby leading to cell transformation, proliferation, inhibition to apoptosis, and promotion of cell survival, and finally resulting in formation of tumor. Therefore, in recent years, the development trend of antineoplastic agents begins to turn to drugs for abnormal intracellular signaling from conventional cytotoxic drugs, and some relevant drugs have been used in clinic in succession. Compared with conventional cytotoxic antineoplastic agents, this type of molecular targeted agents have strong efficacy and less toxic and side effects, and have gradually become hot issues in current research and development of antineoplastic agents.
The tyrosine kinases are classified into receptor tyrosine kinases and non-receptor tyrosine kinases. The receptor tyrosine kinases include epithelial growth factor receptor (EGFR) family, vascular endothelial growth factor (VEGFR) family, platelet derived growth factor receptor (PDGFR) family, fibroblast growth factor receptor (FGFR) family, and so on. The non-receptor tyrosine kinases include Src kinase family, Jak, FAK, and so on. Each kinase family further includes a variety of subtypes.
Hepatocyte growth factor receptor c-Met is a type of receptor tyrosine kinase (Park et al., Proc. Natl. Acad. Sci. USA 84: 6379-83, 1987; Bottaro et al., Science 2S 1: 802-4, 1991), and includes highly glycosylated outer α subunits and β subunits, and extracellular domains, transmembrane segments and cytoplasmic tyrosine kinase domains. The endogenous ligand for c-Met is hepatocyte growth factor (HGF) (Nature, 327: 239-242 (1987); J. Cell Biol., 111: 2097-2108 (1990)), and c-Met binds with the ligand to induce dimerization of c-Met, so as to generate an autophosphorylated activated receptor, promote downstream signaling, and mediate a variety of responses in tumor cells, including proliferation of epithelial cells and endothelial cells, stimulation of epithelial cell motility, cell survival and morphological changes and promotion of invasion. In addition, HGF regulates angiogenesis, has important meaning for tumor growth and spread. Overexpression of c-Met and the ligand thereof in a variety of tumors (including thyroid cancer, ovarian cancer and pancreatic cancer) also indicates the role of c-Met and the ligand thereof in the development of these tumors.
Presently, in primary tumor and secondary tumor metastasis that c-Met receptor activation plays a key role, a biomass (ribozyme, antibody and antisense RNA) of targeting HGF or c-Met can inhibit tumorigenesis, and it is predicted that selective small-molecular inhibitors of targeting c-Met has therapeutic potential. Patents WO2004/076412, WO2006/021881, WO2010/011538, WO2010/059771 and WO2010/048131 disclose selective c-Met small-molecular inhibitors, and preparation methods and uses thereof.
The heterocyclic pyridone compound disclosed in the present invention has not been reported as a tyrosine kinase inhibitor, a tyrosine kinase inhibitor, especially a c-Met inhibitor.